Regio- and Stereodivergent Allylic Reductions of Bicyclic Piperidine Enecarbamate Derivatives (original) (raw)

2018, The Journal of Organic Chemistry

The particular nature of tetrahydropyrido[4,3-e]-1,4,2-dioxazines of type 1 allows the regio-and stereoselective obtainment of substituted N-carbamoyl tetrahydropyridines by common reducing agents. A completely novel, biologically active, bicyclic 1,3-diaza-4-oxa-[3.3.1]-nonene scaffold can be generated by the use of lithium triethylborohydride through an unprecedented cascade syn-SN2' reduction/carbamate reduction/cyclization reactions. The remarkable regioselectivity switches of allylic reduction process have been rationalized with the aid of computational studies. Tetrahydropyridines are important targets in synthetic organic chemistry due to their relevance as privilege structure in medicinal chemistry. 1 Therefore, considerable efforts have been devoted to the individuation of new methods for their regio-and stereoselective synthesis and functionalization. 2 However, a regio-and stereodivergent reduction of piperidine enecarbamates bearing an allylic leaving group has not yet been reported. The main reason for this shortcoming can be found in the relative instability of 1,2,3,4tetrahydropyridine derivatives containing common leaving groups at the C4-position. We recently became interested in the elaboration of nitroso cycloadducts derived from 2substituted-1,2-dihydropyridines, 3 easily accessible by addition of nucleophiles to activated pyridinium salts (eq. a, Scheme 1). 4,5 The [3,3]-hetero Cope rearrangement of the obtained nitroso Diels-Alder (NDA) cycloadducts has been reported to give 4a,7,8,8atetrahydropyrido[4,3-e]-1,4,2-dioxazines of type 1 (eq. a, Scheme 1). 6 We noticed that the study of their reactivity is limited to the NO reductive cleavage with Raney nickel to obtain racemic aminoarabinose and aminoaltrose derivatives. 6a On the other hand, palladiumcatalyzed allylic reduction have been used extensively in synthetic organic chemistry to